Rapid syntheses of N-fused heterocycles via acyl-transfer in heteroaryl ketones

The wide-ranging potencies of bioactive N-fused heterocycles inspire the development of synthetic transformations that simplify preparation of their complex, diverse structural motifs. Heteroaryl ketones are ubiquitous, readily available, and inexpensive molecular scaffolds, and are thus synthetically appealing as precursors in preparing N-fused heterocycles via intramolecular acyl-transfer. To best of our knowledge, acyl-transfer of unstrained heteroaryl ketones remains to be demonstrated. Here, we show an acyl transfer-annulation to convert heteroaryl ketones to N-fused heterocycles. Driven via aromatisation, the acyl of a heteroaryl ketone can be transferred from the carbon to the nitrogen of the corresponding heterocycle. The reaction commences with the spiroannulation of a heteroaryl ketone and an alkyl bromide, with the resulting spirocyclic intermediate undergoing aromatisation-driven intramolecular acyl transfer. The reaction conditions are optimised, with the reaction exhibiting a broad substrate scope in terms of the ketone and alkyl bromide. The utility of this protocol is further demonstrated via application to complex natural products and drug derivatives to yield heavily functionalised N-fused heterocycles.

Acyl transfer is a critical process in various biological transformations 13 . In the field of organic synthesis, acyl transfer is frequently used in formation carbonyl compounds [14][15][16][17][18] . A typical acyl transfer employs a reactive carboxylic acid derivative (e.g. an acyl chloride or a thioester) as an acyl source. However, whether relatively inert ketones may serve as acyl transfer agents remains unclear?
Ketones are ubiquitous functional groups that not only occur widely in drug molecules and natural products but also act as bulk feedstocks in the syntheses of fine chemicals and materials. They are stable, non-toxic, and simple to prepare via various methods, rendering them ideal synthetic precursors 19 . If intramolecular acyl transfer of heteroaryl ketones can be realised, a transfer-annulation strategy may be employed in N-fused heterocycle preparation (Fig. 1b). However, owing to the kinetic inertness of C-C bonds, acyl transfer of ketones largely focuses on highly strained ketones [20][21][22][23][24][25][26] . For unstrained ketones [27][28][29][30][31][32] , the most common strategy involves using directing groups to form of a stable chelate ( Fig. 1c) [33][34][35][36][37][38][39][40] . Although effective, the use of directing groups complicates the overall synthesis and limits the scope of the accessible products. Hence, a acyl transfer of unstrained ketones for use in N-fused heterocycle synthesis is warranted.
Aromatisation, which enables delocalisation of electron density, stabilising the molecule 41 , is a critical thermodynamic driving force in the field of organic chemistry [42][43][44][45] , e.g. aromatisationdriven deacylations of ketones are prominent bond-cleavage strategies [46][47][48] . Therefore, we conceived a approach for the acyl transfer of unstrained heteroaryl ketones driven by aromatisation of a pre-aromatic intermediate (Fig. 1d). This strategy may be suitable for use in the syntheses of N-fused heterocycles, and, critically, the directing group is no longer required. The next challenge in this strategy is the in situ formation of special, highenergy, pre-aromatic substrates. Transition metal-catalysed dearomatisation is a straightforward strategy to prepare spirocyclic scaffolds [49][50][51][52] . The spirocyclic intermediates, which are formed in situ from readily available heteroaryl ketones via dearomatisations [53][54][55][56] , should serve as pre-aromatic precursors to facilitate rearrangement (Fig. 1d). This likely involves a Pdcatalysed dearomative spirocyclisation of a heteroaryl ketone with an alkyl bromide to generate a pre-aromatic intermediate (A), which is then intramolecularly trapped by the heterocyclic nitrogen [57][58][59][60][61] . The resulting intermediate (B) may subsequently lose a hydrogen, restoring aromaticity to yield the fused heterocyclic product.
Here, we report an acyl transfer-annulation of heteroaryl ketones driven by aromatisation. This method is operationally simple, scalable, and applicable to late-stage modifications of natural products and drug derivatives, which make it a valuable method for the synthesis of organic N-fused heterocycles.

Results
Reaction optimisation. To explore this strategy, we initially used a heteroaryl ketone with a tethered olefin (1), which was prepared in one step using commercially available benzimidazole and 2-vinylbenzoyl chloride, as a model substrate. Because of the unique properties of difluoromethylene group (CF 2 ) and its critical applications in medicinal chemistry [62][63][64] , ethyl bromodifluoroacetate (BrCF 2 COOEt) was employed as the coupling partner. After systematic screening, the desired rearrangement product (2) is obtained in a 90% yield using PdCl 2 in combination with 1,1-bis(diphenylphosphino)pentane (dpppent, L1) as the ligand and Na 2 CO 3 as the base in dioxane/tetrahydrofuran (THF) ( Table 1, entry 1). The structure of 2 was unambiguously determined by X-ray crystallography. In addition, the Pd catalyst appears to be critical in this reaction.
Mechanistic considerations. A study was performed to investigate the reaction pathway. To determine whether an alkyl radical   exists during this Pd-catalysed process, a radical inhibition study was performed. When 2,2,6,6-tetramethylpiperidinooxy (TEMPO) is added to the reaction mixture, it traps alkyl radicals, indicating that the reaction involves radical species (Fig. 4a). An electron paramagnetic resonance (EPR) study of the reaction of bromocyclopentane with the spin-trapping agent phenyl-N-tertbutylnitrone reveals the presence of spin adducts of the trapped alkyl radicals 56 and 57 (Fig. 4b), as indicated by the EPR spectrum (see supporting information). Deuterium labelling studies were conducted using the heteroaryl ketone D-1 (79% deuterium content) as a substrate under the optimised conditions, with a significant level of the deuterated product D-2 (76% deuterium content) detected, suggesting that there were no reversible hydro-metallation in this process (Fig. 4c) 67,68 . Finally, we synthesised an aryl Pd complex (58-[Pd]), with 12 produced instead of 59 in the presence of 58-[Pd], benzyl bromide, and 1 (Fig. 4d). Therefore, the alkyl group of the fused heterocyclic product is not derived from the migratory insertion of the Pd(II) complex. The proposed reaction pathway is thus shown in Fig. 4e. The reaction may be initiated by a single electron transfer between Pd(0) and the alkyl bromide, producing hybrid alkyl Pd(I)-radical species INT I. Subsequently, radical addition to the alkene occurs, leading to the hybrid benzylic radical INT II, which then undergoes dearomatisative-spirocyclisation to form the spiro-N-radical INT III. Aromatisation-driven intramolecular acyl transfer may then occur to form the alkyl radical INT IV. Subsequent β-H elimination at the latter yields the product with concomitant regeneration of the Pd catalyst. This proposed mechanism is also supported by X-ray photoelectron spectroscopy, which revealed the presence of three distinct Pd oxidation states (Pd(0), Pd(I), and Pd(II)) during the process, suggesting that Pd(I) species may be involved.
Synthetic utility. Further studies were conducted to demonstrate the viability of this acyl transfer-annulation strategy. The protocol was applied in the late-stage modifications of natural products and drug derivatives (Fig. 5a). Various complex molecules with diverse structural features, such as steroids (62 and 69), N-heteroarenes (oxazole 63 and indole 68), alkaloids (66), and carbohydrates (72), are readily converted into the corresponding products in useful yields. This strategy provides a straightforward, versatile method of generating valuable N-fused heterocyclic moieties within complex molecules. Given the ubiquity of Nfused heterocycles in pharmaceuticals, this approach may be used in the field of medicinal chemistry.
To showcase the scalability of this process, a gram-scale reaction was carried out. Gratifyingly, a satisfactory 67% isolated yield (80% yield based on recovered 1) of product 2 could be obtained without modification of the optimised conditions (Fig. 5b). The N-fused heterocyclic scaffold can readily undergo various transformations to access a range of synthetically useful scaffolds. For example, the bromination of 2 proceeded to afford 74, excellent selectivity for the 9-position was observed, which allows follow-up fused heterocycle manipulations through cross-couplings. Treatment with mCPBA, deconstruction of N-fused heterocycle was observed, which afforded 75 in 53% yield. Diazidation product 76 was afforded in 48% yield via vicinal diazidation of olefin. Moreover, the ester moiety was smoothly reduced with NaBH 4 , affording the corresponding alcohol 77 in 68% yield.
In conclusion, a synthetically useful, mechanistically intriguing intramolecular acyl transfer of heteroaryl ketones was developed, which was suitable for use in fused-ring synthesis. The formation of a high-energy pre-aromatic spirocyclic intermediate was critical in the successful transformation, with aromatisation the driving force that facilitated C-C bond cleavage. Given the ready availability of the ketone moiety, this strategy could be used to simplify the syntheses of complex N-fused heterocyclic systems, which are privileged structures within numerous biologically active compounds. Moreover, the protocol enabled the late-stage modifications of intricate natural products and drug derivatives and may thus facilitate heterocyclic drug discovery.

Methods
General condition A for transfer-annulation of heteroaryl ketones derived from (benzo)imidazoles. In a nitrogen-filled glovebox, an oven-dried 10 mL sealed tube equipped with a Teflon-coated magnetic stir bar was charged successively with heteroaryl ketone 1 (0.1 mmol), alkyl bromide (0.15 mmol, 1.5 equiv), PdCl 2 (0.01 mmol, 10 mol%), dpppent (0.012 mmol, 12 mol%), Na 2 CO 3 (0.1 mmol, 1.0 equiv) and dioxane/THF (1.0 mL, 1:2). The tube then was sealed with a Teflon screw cap, moved out of the glovebox, and placed on a hotplate pre-heated to 130°C for 24-36 h. After completion of the reaction, the mixture was filtered through a thin pad of silica gel. The filter cake was washed with ethyl acetate and the combined filtrate was concentrated under vacuum. The residue was purified via silica gel chromatography.
General condition B for transfer-annulation of heteroaryl ketones derived from (benzo)thiazoles and (benzo)oxazoles. In a nitrogen-filled glovebox, an oven-dried 10 mL sealed tube equipped with a Teflon-coated magnetic stir bar was charged successively with heteroaryl ketone 1 (0.1 mmol), difluorobromoethyl ester (0.15 mmol, 1.5 equiv), PdCl 2 (0.01 mmol, 10 mol%), dppf (0.012 mmol, 12 mol%), K 2 CO 3 (0.1 mmol, 1.0 equiv) and dioxane/THF (1.0 mL, 1:1). The tube then was sealed with a Teflon screw cap, moved out of the glovebox, and placed on a hotplate pre-heated to 120°C for 24 h. After completion of the reaction, the mixture was filtered through a thin pad of silica gel. The filter cake was washed with ethyl acetate and the combined filtrate was concentrated under vacuum. The residue was purified via silica gel chromatography.

Data availability
Data relating to the optimisation studies, mechanistic studies, general methods, and the characterisation data of materials and products, are available in the Supplementary